The term “epigenetics” refers to modifications in gene expression that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure. DNA is complexed with histone proteins to form the nucleosome subunits of chromatin. In the basic nucleosome structure, 147 base pairs of DNA are wrapped around an octamer of histone proteins H2A, H2B, H3, and H4. Histones are posttranslationally modified by methylation, acetylation, phosphorylation, and ubiquitination. And these posttranslational modifications have been shown to have regulatory effects on chromatin structure and gene transcription (Workman 2006). Thus, posttranslational modification of histones have epigenetic effects.
Acetylation of histones is accomplished by histone acetyltransferases (HATs). Deacetylation of histones is accomplished by histone deacetylases (HDACs). An imbalance of HAT and HDAC activity has been identified in some types of cancer cells (Grigani 1998, Lin 1998, Suzuki 2002). This causes alterations in the acetylation state of histones at certain locations in the chromosomes and changes in gene transcription (McLaughlin 2004).
HATs are a diverse set of enzymes. One subfamily of HATs is the Gcn5 N-acetyl transferases, including Gcn5, PCAF, Elp3, Hat1, Hpa2, and Nut1 (reviewed in Kimura 2005). Another family of HATs is the MYST HATs, including Morf, Ybf2, Sas2, and Tip60 (reviewed in Kimura 2005). Other HATs include p300/CBF and Taf1. The variety of HAT enzymes is further complicated by the fact that HATs reside in multiprotein complexes with other subunits, and changes in the subunit composition of a complex affect HAT activity and specificity.
Histone deacetylases are complex as well. Histone deacetylases are grouped into three classes based on homology with yeast deacetylases. Class I histone deacetylases include HDAC1, HDAC2, HDAC3 and HDAC8 and are homologous to yeast RPD3. Class II histone deacetylases have several members and are homologous with yeast Hda1. The third class of human histone deacetylases has seven members homologous to yeast Sir2 (Thiagalingam 2003)
Histone acetylation activates transcription and deacetylation silences genes, in general. (Berger 2002). Histone acetylation and other histone modification has been shown to regulate the activity of genes involved in tumorigenesis (Suzuki 2002; Glaser 2003).
The activity of HATs and HDACs varies depending on several factors, including the methylation state of the histone substrate, the amino acid residue in the histone being acetylated or deacetylated, and the chromosome position of the histones. (Cheung 2000, Qin 2006, Gilbert 2007, Lorincz 2001, Espada 2004)
With the emerging importance of histone acetylation and deacetylation in normal gene regulation and aberrant gene regulation in cancer and other diseases, improved tools to characterize the activity and specificity of enzymes catalyzing acetylation and deacetylation of histones and other proteins are needed.